Even though significant advances have occurred in the treatment of cancer, it still remains a major health concern. Cancer has been reported as the leading cause of death in the United States with one of every four Americans likely to be diagnosed with the disease. By way of example, colorectal cancer is the third most commonly diagnosed cancer in the world that accounts for approximately 600,000 deaths per year. While a colonoscopy allows for the early detection of the disease and the identification of individuals who are at high risk of disease progression, the mortality rate from colorectal cancer has decreased only marginally in the last two decades (1). Additionally, certain lesions such as flat adenomas cannot be readily detected by a colonoscopy (2) and surgical management of adenomas in high risk individuals, such as with familial adenomatous polyposis (FAP) often requires complete or segmental removal of the colon (3). Given the slow progression of carcinogenesis and the limitations of colonoscopy, much research has focused on cancer chemoprevention to reduce the development and progression of colorectal cancer.
Included among the known chemotherapeutic drugs are carmustine, doxorubicin, methotrexate, paclitaxel, cyclophosphamide, procarbazine, and vinblastine, to name only a few. However, many chemotherapeutic drugs also produce undesirable side effects in the patient.
Certain nonsteroidal anti-inflammatory drugs (NSAIDs) have been recognized to have broad anticancer activity in animal models alone and in combination with chemotherapy or radiation. Representative examples include: Hial et al., “Alteration of tumor growth by aspirin and indomethacin: studies with two transplantable tumors in mouse” Eur. J. Pharm. 37: 367-376, 1976; Lynch et al., “Mechanism of inhibition of tumor growth by aspirin and indomethacin” Br. J. Cancer 38: 503-512, 1978; Bennett et al., “Increased survival of cancer-bearing mice treated with inhibitors of prostaglandin synthesis alone or with chemotherapy” Br. J. Cancer 45: 762-768, 1982; Pollard and Luckert “Prolonged antitumor effect of indomethacin on autochthonous intestinal tumors in rats” J. Natl. Cancer Inst. 70: 1103-1105, 1983; Fulton, “Inhibition of experimental metastasis with indomethacin: role of macrophages and natural killer cells” Prostaglandins: 35: 413-425, 1988; Moorghen et al., “The effect of sulindac on colonic tumor formation in dimethylhydrazine-treated mice” Acta histochemica 29: 195-199, 1990; and Moorghen et al., “A protective effect of sulindac against chemically-induced primary colonic tumours in mice” J. of Path. 156: 341-347.
Epidemiological studies have shown that long-term use of NSAIDs can significantly reduce the incidence and risk of death from colorectal cancer (4). In addition, certain prescription strength NSAIDs, such as sulindac can cause the regression and prevent recurrence of adenomas in individuals with FAP (5). The antineoplastic activity of NSAIDs is widely attributed to their cyclooxygenase (COX) inhibitory activity because prostaglandins are elevated in colon tumors (6) and a significant percentage of colon tumors express high levels of the inducible COX-2 isozyme (7). However, there is evidence that alternative mechanisms either contribute to or fully account for the colorectal cancer chemopreventive activity of NSAIDs (8-10). For example, the non-COX inhibitory sulfone metabolite of sulindac has been reported to inhibit the growth and induce apoptosis of colon tumor cell in vitro (11, 12) and suppress colon tumorigenesis in animal models (13-15). Sulindac sulfone (exisulind) was also shown to suppress adenoma formation in individuals with FAP or sporadic adenomas (16, 17), but did not receive FDA approval due to hepatotoxicity. The use of NSAIDs is associated with gastrointestinal, renal and cardiovascular toxicities from suppressing prostaglandin synthesis (18, 19).
Previous studies have shown that certain NSAIDs can decrease nuclear levels of β-catenin by inducing proteosomal degradation to inhibit the transcription of genes (e.g. cyclin D, survivin) that provide a survival advantage to allow for clonal expansion of neoplastic cells (20-22). Several groups have reported that sulindac sulfone can also induce the degradation of oncogenic β-catenin, which suggests that the underlying biochemical mechanism by which NSAIDs suppress β-catenin signaling may not require COX inhibition (22-24).
As mentioned above, Sulindac (Clinoril™) is a NSAID that has demonstrated anticancer activity. It has been recognized as having benefits for treating precancerous conditions as evidenced by a number of clinical trials in familial adenomatous polyposis patients which have shown the ability of sulindac to cause the regression of existing adenomas (size and number) and to inhibit new adenoma (polyp) formation. For example, see Waddell et al, “Sulindac for polyposis of the colon”. J. of Surg. 157: 175-179, 1989; Labayle et al., “Sulindac causes regression of rectal polyps in familial adenomatous polyposis” Gastroenterology 101: 635-639, 1991; Nugent et al., “Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis” Br. J. Surg. 80: 1618-1619, 1993; Giardiello, et al., “Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis” N. Eng. J. Med 328: 1313-6, 1993; and Winde et al., “Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment.” Dis. Colon Rectum 38: 813-830, 1995.
The mechanism responsible for the anti-inflammatory efficacy and the toxicity of NSAIDs and COX-2 selective inhibitors (gastrointestinal, renal, hematological, cardiovascular) has been shown to involve cyclooxygenase COX-1 or COX-2 inhibition. Sulindac and certain other NSAIDs also have hepatic toxicity. For instance, see Vane, “Mode of action of aspirin and similar compounds” In Prostaglandin Synthetase Inhibitors, Eds Robinson, Raven Press, New York, N.Y., 1974; Eaker “Gastrointestinal injury related to the use of nonsteroidal anti-inflammatory drugs” Gastrointestinal Disease Today 6: 1-8, 1997; Wolfe et al., “Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs” N. Eng. J. Med 340: 1888-99, 1999; Palmer “Renal complications associated with use of nonsteroidal anti-inflammatory agents” J. Invest. Medicine 43: 516-533, 1995; Tarazi et al., “Sulindac-associated hepatic injury: analysis of 91 cases reported to the Food and Drug Administration” Gastroenterology 104: 569-574, 1993; and Mukherjee et al. “Risk of cardiovascular events associated with selective COX-2 inhibitors” JAMA 286: 954-959, 2001.
Most investigators attribute the mechanism for the anticancer activity of NSAIDs to anti-inflammatory activity involving COX inhibition, although there is some evidence for a COX-independent mechanism as mentioned below. For example, the activity of the sulfone metabolite of sulindac has been described which retains anticancer activity in preclinical and clinical trials but does not inhibit cyclooxygenase and displays less GI toxicity. See for example, Piazza et al., “Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis” Cancer Res. 55: 3110-3116, 1995; Piazza et al., “Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels” Cancer Res. 57: 2909-2915, 1997; Piazza et al., “Apoptosis primarily accounts for the growth inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction” Cancer Res. 57: 2452-2459, 1997; Piazza et al, “Exisulind a novel proapoptotic drug inhibits rat urinary bladder tumorigenesis” Cancer Res., 61: 3961-3968, 2001; and Chan “Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention” The Lancet Oncology 3: 166-174, 2002.
The mechanism responsible for the antineoplastic activity of sulindac sulfone has been previously reported to involve cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibition (23, 25). More recently, it has been reported that the COX inhibitory sulfide metabolite of sulindac and certain other NSAIDs also inhibit cGMP PDE, and that this activity is closely associated with their tumor cell growth inhibitory and apoptosis-inducing properties (26-28). Cyclic nucleotide PDEs are a large superfamily of enzymes responsible for regulating second messenger signaling by hydrolyzing the 3′,5′-phosphodiester bond in cGMP and/or cAMP. There are at least eleven PDE isozyme family members having different substrate specificities, regulatory properties, tissue localization, and inhibitor sensitivity (29). PDE1, 2, 3, 10 and 11 are dual substrate-degrading isozymes, while PDE5, 6, and 9 are selective for cGMP and PDE4, 7, and 8 are cAMP selective. In addition, each isozyme family contains multiple isoforms or splice variants. Depending on the PDE isozyme content of the target cell population and inhibitor selectivity, PDE inhibitors can increase the magnitude and/or the duration of the cAMP and/or cGMP intracellular signal(s). Increasing cyclic nucleotide levels can induce specific signaling pathways, which, in the case of cGMP, can activate protein kinase G (PKG) to regulate cellular activity (30).
There are publications suggesting that certain chemical modifications to the carboxylic acid moiety of NSAIDs will result in improved safety (i.e., as prodrugs or by localized release of nitric oxide). For example, see Mahmud et al., “A unifying hypothesis for the mechanism of NSAID related gastrointestinal toxicity”. Ann. Rheumatic Diseases 55: 211-213, 1996; Venuti et al., “Synthesis and biological evaluation of (N,N,N,-trialkylammonium)alkyl esters and thioesters of carboxylic acid nonsteroidal anti-inflammatory drugs” Pharmaceutical Research 6: 867-873, 1989; Salimbeni et al., “New esters of N-arylanthranilic acids” Farmaco 30: 276-86, 1975; and Elliot et al. “A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats” Gastroenterology 109: 524-530, 1995.
In addition, U.S. Pat. Nos. 5,401,774, 6,166,053 and 6,200,771 suggest certain modifications to sulindac sulfone which is not a NSAID.
As another example, a series of amide and ester derivatives of indomethacin and meclofenamic acid involving modifications to the carboxylic acid moiety were described by Marnett et al. These compounds were described as having safety advantages over the parent NSAIDs based on selectivity for the cyclooxygenase-2 isozyme. However, anticancer activity was not described and modifications to improve anticancer efficacy (potency) were not described. For example, see Kalgutkar et al., “Biochemical based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal anti-inflammatory drugs to potent and highly selective COX-2 inhibitors” Proc. Natl. Acad. Sci. 97: 925-930, 2000; Kalgutkar et al. “Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors” Bioorganic and Medicinal Chemistry Letters 12: 521-524, 2002; Kalgutkar et al., “Ester and amide derivatives of the nonsteroidal anti-inflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors” J. Med. Chem. 43: 2860-2870, 2000; U.S. Pat. No. 5,973,191 to Marnett and Kalgutkar “Selective inhibitors of prostaglandin endoperoxide synthetase-2”; and U.S. Pat. No. 5,475,021 to Marnett and Kalgutkar “Compounds and compositions for inhibition of cyclooxygenase activity”.
More recently, various amide derivatives of sulindac have been disclosed in U.S. patent application Ser. No. 60/755,847 filed Jan. 4, 2006 and Ser. No. 11/649,373 filed Jan. 4, 2007, now U.S. Pat. No. 8,044,048 to Piazza et al. and assigned to Southern Research Institute, the assignee of the present application. However, during animal testing, modest metabolism of the amide linkage from at least one of the amide derivatives of sulindac was noted, producing sulindac sulfide a known COX 1 and COX 2 inhibitor. Production of this product is likely a result of non-specific enzymes known as amidases that can regenerate the carboxylic acid and can cause side effects resulting from COX inhibition. The metabolism of the amide to the carboxylic acid has been previously reported by Piazza et al, “A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits tumor cell growth and induces apoptosis with antitumor activity” Cancer Prev. Res. 2: 574-580, 2009.
Notwithstanding the advances in treatments for cancer and other diseases there still remains an unmet medical need for improved drugs that are effective for the prevention and treatment of cancer, while at the same time exhibiting reduced adverse side effects.